Quercetin and dasatinib, two powerful senolytics in age-related cardiovascular disease.

Cellular senescence is characteristic of the development and progression of multiple age-associated diseases. Accumulation of senescent cells in the heart contributes to various age-related pathologies. Several compounds called senolytics have been designed to eliminate these cells within the tissues. In recent years, the use and study of senolytics increased, representing a promising field for finding accessible and safe therapies for cardiovascular disease (CVD) treatment. This mini-review discusses the changes in the aging heart and the participation of senescent cells in CVD, as well as the use of senolytics to prevent the progression of myocardial damage, mainly the effect of dasatinib and quercetin. In particular, the mechanisms and physiological effects of senolytics therapies in the aged heart are discussed.

A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease.

BACKGROUND: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. METHODS: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat (ITT) population. Follow-up was extended to 12 months. RESULTS: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P = .0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. CONCLUSIONS: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days. CLINICAL TRIALS REGISTRATION: NCT02498782.

MicroRNA Dysregulation in Early Breast Cancer Diagnosis: A Systematic Review and Meta-Analysis.

Breast cancer continues to be the leading cause of death in women worldwide. Mammography, which is the current gold standard technique used to diagnose it, presents strong limitations in early ages where breast cancer is much more aggressive and fatal. MiRNAs present in numerous body fluids might represent a new line of research in breast cancer biomarkers, especially oncomiRNAs, known to play an important role in the suppression and development of neoplasms. The aim of this systematic review and meta-analysis was to evaluate dysregulated miRNA biomarkers and their diagnostic accuracy in breast cancer. Two independent researchers reviewed the included studies according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. A protocol for this review was registered in PROSPERO with the registration number "CRD42021256338". Observational case-control-based studies analyzing concentrations of microRNAs which have been published within the last 10 years were selected, and the concentrations of miRNAs in women with breast cancer and healthy controls were analyzed. Random-effects meta-analyses of miR-155 were performed on the studies which provided enough data to calculate diagnostic odds ratios. We determined that 34 microRNAs were substantially dysregulated and could be considered biomarkers of breast cancer. Individually, miR-155 provided better diagnostic results than mammography on average. However, when several miRNAs are used to screen, forming a panel, sensitivity and specificity rates improve, and they can be associated with classic biomarkers such us CA-125 or CEA. Based on the results of our meta-analysis, miR-155 might be a promising diagnostic biomarker for this patient population.

ER membranes associated with mitochondria: Possible therapeutic targets in heart-associated diseases.

Cardiovascular system cell biology is tightly regulated and mitochondria play a relevant role in maintaining heart function. In recent decades, associations between such organelles and the sarco/endoplasmic reticulum (SR) have been raised great interest. Formally identified as mitochondria-associated SR membranes (MAMs), these structures regulate different cellular functions, including calcium management, lipid metabolism, autophagy, oxidative stress, and management of unfolded proteins. In this review, we highlight MAMs' alterations mainly in cardiomyocytes, linked with cardiovascular diseases, such as cardiac ischemia-reperfusion, heart failure, and dilated cardiomyopathy. We also describe proteins that are part of the MAMs' machinery, as the FUN14 domain containing 1 (FUNDC1), the sigma 1 receptor (Sig-1R) and others, which might be new molecular targets to preserve the function and structure of the heart in such diseases. Understanding the machinery of MAMs and its function demands our attention, as such knowledge might contribute to strengthen the role of these relative novel structures in heart diseases.

Replicating the complexity of natural surfaces: technique validation and applications for biomimetics, ecology and evolution.

The surfaces of animals, plants and abiotic structures are not only important for organismal survival, but they have also inspired countless biomimetic and industrial applications. Additionally, the surfaces of animals and plants exhibit an unprecedented level of diversity, and animals often move on the surface of plants. Replicating these surfaces offers a number of advantages, such as preserving a surface that is likely to degrade over time, controlling for non-structural aspects of surfaces, such as compliance and chemistry, and being able to produce large areas of a small surface. In this paper, we compare three replication techniques among a number of species of plants, a technical surface and a rock. We then use two model parameters (cross-covariance function ratio and relative topography difference) to develop a unique method for quantitatively evaluating the quality of the replication. Finally, we outline future directions that can employ highly accurate surface replications, including ecological and evolutionary studies, biomechanical experiments, industrial applications and improving haptic properties of bioinspired surfaces. The recent advances associated with surface replication and imaging technology have formed a foundation on which to incorporate surface information into biological sciences and to improve industrial and biomimetic applications. This article is part of the theme issue 'Bioinspired materials and surfaces for green science and technology'.

Cytidine-5'-Diphosphocholine Protects the Liver From Ischemia/Reperfusion Injury Preserving Mitochondrial Function and Reducing Oxidative Stress.

Cytidine-5'-diphosphocholine (CDP-choline) participates as an intermediary in the synthesis of phosphatidylcholine, an essential component of cellular membranes. Citicoline treatment has shown beneficial effects in cerebral ischemia, but its potential to diminish reperfusion damage in liver has not been explored. In this work, we evaluated the hepatoprotective effect of citicoline and its possible association with inflammatory/oxidative stress and mitochondrial function because they are the main cellular features of reperfusion damage. Ischemia/reperfusion (I/R) in rat livers was performed with the Pringle's maneuver, clamping the 3 elements of the pedicle (hepatic artery, portal vein, and biliary tract) for 30 minutes and then removing the clamp to allow hepatic reperfusion for 60 minutes. The I/R + citicoline group received the compound before I/R. Liver injury was evaluated by measuring aspartate aminotransferase and alanine aminotransferase as well as lactic acid levels in serum; proinflammatory cytokines, proresolving lipid mediators, and nuclear factor kappa B content were determined as indicators of the inflammatory response. Antioxidant effects were evaluated by measuring markers of oxidative stress and antioxidant molecules. Oxygen consumption and the activities of the respiratory chain were used to monitor mitochondrial function. CDP-choline reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as lactic acid levels in blood samples from reperfused rats. Diminution in tumor necrosis factor alpha (TNF-α) and increase in the proresolving lipid mediator resolvin D1 were also observed in the I/R+citicoline group, in comparison with the I/R group. Oxidative/nitroxidative stress in hepatic mitochondria concurred with deregulation of oxidative phosphorylation, which was associated with the loss of complex III and complex IV activities. In conclusion, CDP-choline attenuates liver damage caused by ischemia and reperfusion by reducing oxidative stress and maintaining mitochondrial function. Liver Transplantation XX XX-XX 2018 AASLD.

The secretory phenotype of senescent astrocytes isolated from Wistar newborn rats changes with anti-inflammatory drugs, but does not have a short-term effect on neuronal mitochondrial potential.

In the central nervous system (CNS), senescent astrocytes have been associated with neurodegeneration. Senescent cells secrete a complex mixture of pro-inflammatory factors, which are collectively called Senescence Associated Secretory Phenotype (SASP). The SASP components can vary depending on the cell type, senescence inducer and time. The SASP has been mainly studied in fibroblasts and epithelial cells, but little is known in the context of the CNS. Here, the SASP profile in senescent astrocytes isolated from Wistar newborn rats induced to senescence by oxidative stress or by proteasome inhibition was analyzed. Senescent astrocytes secreted predominantly chemokines and IL-1α, but no IL-6. The effect of the anti-inflammatory drugs, sulforaphane (SFN) and dehydroepiandrosterone (DHEA), on the SASP profile was evaluated. Our results showed that SFN and DHEA decreased IL-1α secretion while increasing IL-10, thus modifying the SASP to a less anti-inflammatory profile. Primary neurons were subjected to the conditioned media obtained from drug-treated senescent astrocytes, and their mitochondrial membrane potential was evaluated.

Vascular epiphytes and host trees of ant-gardens in an anthropic landscape in southeastern Mexico.

Ant-gardens (AGs) are considered one of the most complex mutualist systems between ants and plants, since interactions involving dispersal, protection, and nutrition occur simultaneously in them; however, little is known about the effects of the transformation of ecosystems on their diversity and interactions. In five environments with different land use within an anthropic landscape in southeastern Mexico, we investigated the diversity and composition of epiphytes and host trees of AGs built by Azteca gnava. A total of 10,871 individuals of 26 epiphytic species, associating with 859 AGs located in 161 host trees, were recorded. The diversity and composition of epiphytes tended to be different between environments; however, Aechmea tillandsioides and Codonanthe uleana were the most important species and considered true AG epiphytes, because they were the most frequent, abundant, and occurred exclusively in AGs. Other important species were the orchids Epidendrum flexuosum, Coryanthes picturata, and Epidendrum pachyrachis, and should also be considered true AG epiphytes, because they occurred almost exclusively in the AGs. The AG abundance in agroforestry plantations was similar or even greater than in riparian vegetation (natural habitat). The AGs were registered in 37 host species but were more frequent in Mangifera indica and Citrus sinensis. We conclude that true epiphytes of A. gnava AGs persist in different environments and host trees, and even these AGs could proliferate in agroforestry plantations of anthropic landscapes.

Cross-sex hormonal replacement: Some effects over mitochondria.

Transgender is a term for people whose gender identity or expression differs from their natal sex. These individuals often seek cross-hormonal therapy to simulate the individual´s desired gender. However, the use of estrogens and testosterone has side effects such as a higher propensity to cancer, weight changes and cardiovascular diseases. Testosterone has also been linked with hypertension. Still, little is known about the outcomes and prevalence of metabolic perturbations in the trans community. Here we aim to analyze if cross-administering sexual hormones affects heart mitochondrial function. Mitochondria produces the ATP needed for heart function. In fact, different studies show that mitochondrial dysfunction precedes cardiac damage. In this work we used either female rats castrated and injected with testosterone or male rats castrated and injected with estrogens for 4 months. We performed an electrocardiogram, and then we isolated heart mitochondria to measure the rate of oxygen consumption, calcium fluxes, membrane potential, superoxide dismutase activity, lipoperoxidation and cytokines. We detected wide modifications in all parameters associated to cross-hormonal administration.

S-allyl-cysteine triggers cytotoxic events in rat glioblastoma RG2 and C6 cells and improves the effect of temozolomide through the regulation of oxidative responses.

Glioblastoma (GBM) is an aggressive form of cancer affecting the Central Nervous System (CNS) of thousands of people every year. Redox alterations have been shown to play a key role in the development and progression of these tumors as Reactive Oxygen Species (ROS) formation is involved in the modulation of several signaling pathways, transcription factors, and cytokine formation. The second-generation oral alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic drug used to treat of GBM, though patients often develop primary and secondary resistance, reducing its efficacy. Antioxidants represent promising and potential coadjutant agents as they can reduce excessive ROS formation derived from chemo- and radiotherapy, while decreasing pharmacological resistance. S-allyl-cysteine (SAC) has been shown to inhibit the proliferation of several types of cancer cells, though its precise antiproliferative mechanisms remain poorly investigated. To date, SAC effects have been poorly explored in GBM cells. Here, we investigated the effects of SAC in vitro, either alone or in combination with TMZ, on several toxic and modulatory endpoints-including oxidative stress markers and transcriptional regulation-in two glioblastoma cell lines from rats, RG2 and C6, to elucidate some of the biochemical and cellular mechanisms underlying its antiproliferative properties. SAC (1-750 µM) decreased cell viability in both cell lines in a concentration-dependent manner, although C6 cells were more resistant to SAC at several of the tested concentrations. TMZ also produced a concentration-dependent effect, decreasing cell viability of both cell lines. In combination, SAC (1 µM or 100 µM) and TMZ (500 µM) enhanced the effects of each other. SAC also augmented the lipoperoxidative effect of TMZ and reduced cell antioxidant resistance in both cell lines by decreasing the TMZ-induced increase in the GSH/GSSG ratio. In RG2 and C6 cells, SAC per se had no effect on Nrf2/ARE binding activity, while in RG2 cells TMZ and the combination of SAC + TMZ decreased this activity. Our results demonstrate that SAC, alone or in combination with TMZ, exerts antitumor effects mediated by regulatory mechanisms of redox activity responses. SAC is also a safe drug for testing in other models as it produces non-toxic effects in primary astrocytes. Combined, these effects suggest that SAC affords antioxidant properties and potential antitumor efficacy against GBM.

Impaired Ischemia-Reperfusion Responses in the Hearts of Aged Male and Female Offspring of Obese Rats.

Maternal obesity predisposes offspring (F1) to cardiovascular disease. To evaluate basal heart function and ischemia-reperfusion (IR) responses in F1 males and females of obese mothers, female Wistar rats (F0) were fed chow or an obesogenic (MO) diet from weaning through pregnancy and lactation. Non-sibling F1 males and females were weaned to chow at postnatal day (PND) 21 and euthanized at PND 550. Offspring of MO mothers (MOF1) rarely survive beyond PND 650. Hearts were immediately isolated from euthanized F1s and subjected to 30 min ischemia with 20 min reperfusion. Retroperitoneal fat, serum triglycerides, glucose, insulin, and insulin resistance were measured. Baseline left ventricular developed pressure (LVDP) was lower in male and female MOF1 than in controls. After global ischemia, LVDP in control (C) male and female F1 recovered 78 and 83%, respectively, while recovery in MO male and female F1 was significantly lower at 28 and 52%, respectively. Following the IR challenge, MO hearts showed a higher functional susceptibility to reperfusion injury, resulting in lower cardiac reserve than controls in both sexes. Female hearts were more resistant to IR. Retroperitoneal fat was increased in male MOF1 vs. CF1. Circulating triglycerides and insulin resistance were increased in male and female MOF1 vs. CF1. These data show that MO programming reduces F1 cardiac reserve associated with age-related insulin resistance in a sex-specific manner.

Anandamide and WIN 55212-2 Afford Protection in Rat Brain Mitochondria in a Toxic Model Induced by 3-Nitropropionic Acid: an In Vitro Study.

Mitochondrial dysfunction plays a key role in the development of neurodegenerative disorders. In contrast, the regulation of the endocannabinoid system has been shown to promote neuroprotection in different neurotoxic paradigms. The existence of an active form of the cannabinoid receptor 1 (CB1R) in mitochondrial membranes (mitCB1R), which might exert its effects through the same signaling mechanisms as the cell membrane CB1R, has been shown to regulate mitochondrial activity. Although there is evidence suggesting that some cannabinoids may induce protective effects on isolated mitochondria, substantial evidence on the role of cannabinoids in mitochondria remains to be explored. In this work, we developed a toxic model of mitochondrial dysfunction induced by exposure of brain mitochondria to the succinate dehydrogenase inhibitor 3-nitropropionic acid (3-NP). Mitochondria were also pre-incubated with the endogenous agonist anandamide (AEA) and the synthetic CB1R agonist WIN 55212-2 to evaluate their protective effects. Mitochondrial reduction capacity, reactive oxygen species (ROS) formation, and mitochondrial swelling were assessed as toxic markers. While 3-NP decreased the mitochondrial reduction capacity and augmented mitochondrial ROS formation and swelling, both AEA and WIN 55212-2 ameliorated these toxic effects. To explore the possible involvement of mitCB1R activation on the protective effects of AEA and WIN 55212-2, mitochondria were also pre-incubated in the presence of the selective CB1R antagonist AM281, which completely reverted the protective effects of the cannabinoids to levels similar to those evoked by 3-NP. These results show partial protective effects of cannabinoids, suggesting that mitCB1R activation may be involved in the recovery of compromised mitochondrial activity, related to reduction of ROS formation and further prevention of mitochondrial swelling.

Differential survival and growth of wild and cultivated seedlings of columnar cacti: Consequences of domestication.

PREMISE OF THE STUDY: Studies of domestication of cacti in the Tehuacán Valley have identified morphophysiological divergences between wild and cultivated populations. To determine whether such divergences are associated with differential survivorship in xeric and mesic environments characterizing wild and cultivated habitats, respectively, we hypothesized that seedlings from cultivated populations are less tolerant of xeric environments and that differences between wild and cultivated populations are greater in species with higher management intensity. METHODS: We compared size, survivorship, and absolute and relative growth rates (AGRs, RGRs) in shade and humidity gradients of seedlings from wild and cultivated populations of Stenocereus pruinosus, S. stellatus, Polaskia chichipe, and Escontria chiotilla. These species represent a range of management intensity, from highest to lowest, respectively. KEY RESULTS: Seedlings of cultivated populations were larger than those of wild populations in all species studied. The AGRs were significantly different in P. chichipe and E. chiotilla associated with management, whereas the RGRs and seedling survival were significantly different in S. pruinosus and P. chichipe throughout the shade gradient tested. We also found significant differences in seedling survival among humidity treatments in E. chiotilla and among shade treatments in P. chichipe. CONCLUSIONS: Artificial selection favoring larger fruits favors larger seeds and seedlings. Seedling survivorship and growth of managed plants are generally higher in mesic environments apparently because of natural selection associated with habitat conditions. Such differences may contribute to morphophysiological divergences between wild and cultivated populations. Interspecific differences might be associated with adaptations to the natural environments where each species occurs.

Anomalous aortic origin of the left coronary artery.

We present an unusual case of an anomalous left coronary artery arising from the contralateral sinus of Valsalva: a 63-year-old male patient who consulted to our emergency department with 1-week history of progressive dyspnea on exertion with clinical signs of heart failure, associated with lung congestion on the chest X ray and elevated NT-proBNP levels (2000 pg/ml; normal value <150). Doppler echocardiography showed severe dilation of both left atrium and left ventricle, with severe deterioration of LV systolic function (Ejection fraction of 26%), global hypokinesia and a moderate mitral regurgitation with central jet. A cardiac catheterization was performed, which evidenced an anomalous origin of the left main coronary artery from the right coronary sinus with a proximal lesion of nearly 50%. A coronary computed tomographic angiography confirmed the diagnosis of an anomalous origin with an intramyocardial path at the level of the interventricular septum, associated with moderate extrinsic compression. To determine the degree of functional ischemia presented by the left main coronary artery lesion we performed a fractional flow reserve evaluation, resulting in 0.75, which was ranked as significant. An angioplasty with implantation of a drug-eluting stent (with Everolimus) was performed successfully to the target lesion. The patient evolved favorably during hospitalization and was discharged from the medical center to continue outpatient follow-up. Patient remained asymptomatic at 1-month and 6 months, during clinical evaluation, without evidence of ischemia on noninvasive functional assessment.

Presentamos un raro caso de nacimiento anómalo de arteria coronaria izquierda en el seno de Valsalva contralateral. Se trata de un hombre de 63 años que consultó al servicio de emergencias de nuestro centro por disnea progresiva de una semana de evolución, con signos clínicos de insuficiencia cardíaca, asociado a signos de congestión en la radiografía de tórax, y valores de NT-proBNP elevados (2000 pg/ml; valor normal <150). El ecocardiograma Doppler evidenció dilatación grave de la aurícula y del ventrículo izquierdo, con deterioro grave de la función sistólica (fracción de eyección de 26%), hipoquinesia global e insuficiencia mitral moderada con jet central. Se realizó una cinecoronariografía que evidenció el nacimiento anómalo del tronco de arteria coronaria izquierda desde el seno coronario derecho, con una lesión cercana al 50%. Una angiotomografía coronaria confirmó el origen anómalo del vaso coronario, con trayecto intramiocárdico a nivel del septum interventricular asociado a compresión extrínseca moderada. Para determinar el grado de isquemia funcional que presentaba la lesión del tronco coronario izquierdo se evaluó la reserva de flujo fraccional, que arrojó un resultado de 0.75 el cual se consideró significativo, prosiguiendo a angioplastia con implante de stent liberador de droga (con Everolimus) a dicha lesión. El paciente evolucionó favorablemente durante la internación en el hospital, egresando de la institución para continuar seguimiento ambulatorio. Persistió asintomático en los controles realizados al mes y a los 6 meses, sin evidencia de isquemia en la evaluación funcional no invasiva.

Cardiosome-mediated protection in myocardial ischemia.

Cardiosomes, exosomes released in cardiospheres by cardiomyocytes and progenitor cells, communicate locally and at a distance from different tissues, promoting beneficial cellular changes. For example, miRNAs have emerged as regulators of intercellular communication via transport by extracellular vesicles in general and cardiosomes specifically. Although cardiosomes are considered biomarkers owing to their immense biomedical application in various clinical fields, their role in cardiovascular diseases remains unclear. This mini-review examines the experimental and clinical evidence for cardiosomes as non-invasive diagnostic, treatment and prognostic tools in acute myocardial infarction, the novelty of which is often lost in medical practice. In addition, we discuss the potential role of cardiosomes in physiologic mechanisms and cell signaling in cardiac conditioning strategies against reperfusion injury.

Sulforaphane modifies mitochondrial-endoplasmic reticulum associations through reductive stress in cardiomyocytes.

Mitochondria-endoplasmic reticulum (ER) communication relies on platforms formed at the ER membrane with the mitochondrial outer membrane contact sites (MERCs). MERCs are involved in several processes including the unfolded protein response (UPR) and calcium (Ca2+) signaling. Therefore, as alterations in MERCs greatly impact cellular metabolism, pharmacological interventions to preserve productive mitochondrial-ER communication have been explored to maintain cellular homeostasis. In this regard, extensive information has documented the beneficial and potential effects of sulforaphane (SFN) in different pathological conditions; however, controversy has arisen regarding the effect of this compound on mitochondria-ER interaction. Therefore, in this study, we investigated whether SFN could induce changes in MERCs under normal culture conditions without damaging stimuli. Our results indicate that non-cytotoxic concentration of 2.5 µM SFN increased ER stress in cardiomyocytes in conjunction with a reductive stress environment, that diminishes ER-mitochondria association. Additionally, reductive stress promotes Ca2+ accumulation in the ER of cardiomyocytes. These data show an unexpected effect of SFN on cardiomyocytes grown under standard culture conditions, promoted by the cellular redox unbalance. Therefore, it is necessary to rationalize the use of compounds with antioxidant properties to avoid triggering cellular side effects.

Actin-Cytoskeleton Drives Caveolae Signaling to Mitochondria during Postconditioning.

Caveolae-associated signaling toward mitochondria contributes to the cardioprotective mechanisms against ischemia-reperfusion (I/R) injury induced by ischemic postconditioning. In this work, we evaluated the role that the actin-cytoskeleton network exerts on caveolae-mitochondria communication during postconditioning. Isolated rat hearts subjected to I/R and to postconditioning were treated with latrunculin A, a cytoskeleton disruptor. Cardiac function was compared between these hearts and those exposed only to I/R and to the cardioprotective maneuver. Caveolae and mitochondria structures were determined by electron microscopy and maintenance of the actin-cytoskeleton was evaluated by phalloidin staining. Caveolin-3 and other putative caveolae-conforming proteins were detected by immunoblot analysis. Co-expression of caveolin-3 and actin was evaluated both in lipid raft fractions and in heart tissue from the different groups. Mitochondrial function was assessed by respirometry and correlated with cholesterol levels. Treatment with latrunculin A abolishes the cardioprotective postconditioning effect, inducing morphological and structural changes in cardiac tissue, reducing F-actin staining and diminishing caveolae formation. Latrunculin A administration to post-conditioned hearts decreases the interaction between caveolae-forming proteins, the co-localization of caveolin with actin and inhibits oxygen consumption rates in both subsarcolemmal and interfibrillar mitochondria. We conclude that actin-cytoskeleton drives caveolae signaling to mitochondria during postconditioning, supporting their functional integrity and contributing to cardiac adaption against reperfusion injury.

NAC Pre-Administration Prevents Cardiac Mitochondrial Bioenergetics, Dynamics, Biogenesis, and Redox Alteration in Folic Acid-AKI-Induced Cardio-Renal Syndrome Type 3.

The incidence of kidney disease is increasing worldwide. Acute kidney injury (AKI) can strongly favor cardio-renal syndrome (CRS) type 3 development. However, the mechanism involved in CRS development is not entirely understood. In this sense, mitochondrial impairment in both organs has become a central axis in CRS physiopathology. This study aimed to elucidate the molecular mechanisms associated with cardiac mitochondrial impairment and its role in CRS development in the folic acid-induced AKI (FA-AKI) model. Our results showed that 48 h after FA-AKI, the administration of N-acetyl-cysteine (NAC), a mitochondrial glutathione regulator, prevented the early increase in inflammatory and cell death markers and oxidative stress in the heart. This was associated with the ability of NAC to protect heart mitochondrial bioenergetics, principally oxidative phosphorylation (OXPHOS) and membrane potential, through complex I activity and the preservation of glutathione balance, thus preventing mitochondrial dynamics shifting to fission and the decreases in mitochondrial biogenesis and mass. Our data show, for the first time, that mitochondrial bioenergetics impairment plays a critical role in the mechanism that leads to heart damage. Furthermore, NAC heart mitochondrial preservation during an AKI event can be a valuable strategy to prevent CRS type 3 development.

Osthole Prevents Heart Damage Induced by Diet-Induced Metabolic Syndrome: Role of Fructokinase (KHK).

There is increasing evidence that either ingested or produced fructose may have a role in metabolic syndrome. While not commonly considered a criterion for metabolic syndrome, cardiac hypertrophy is often associated with metabolic syndrome, and its presence carries increased cardiovascular risk. Recently it has been shown that fructose and fructokinase C (KHK) can be induced in cardiac tissue. Here we tested whether diet-induced metabolic syndrome causes heart disease associated with increased fructose content and metabolism and whether it can be prevented with a fructokinase inhibitor (osthole). Male Wistar rats were provided a control diet (C) or high fat/sugar diet for 30 days (MS), with half of the latter group receiving osthol (MS+OT, 40 mg/kg/d). The Western diet increased fructose, uric acid, and triglyceride concentrations in cardiac tissue associated with cardiac hypertrophy, local hypoxia, oxidative stress, and increased activity and expression of KHK in cardiac tissue. Osthole reversed these effects. We conclude that the cardiac changes in metabolic syndrome involve increased fructose content and its metabolism and that blocking fructokinase can provide cardiac benefit through the inhibition of KHK with modulation of hypoxia, oxidative stress, hypertrophy, and fibrosis.